The most well-known anthracycline anticancer drugs are doxorubicin and daunorubicin, which contain a 13-keto group. Doxorubicin, disclosed in U.S. Pat. No. 3,590,028, has a wide spectrum of anticancer utility and is used in the treatment of leukemias, lymphomas, and solid tumors. Daunorubicin, disclosed in U.S. Pat. No. 3,616,242, is useful in the treatment of acute leukemias. However, the utility of these drugs is limited by a serious side effect of cardiotoxicity so that the total amount of drug that can be given to a patient cannot exceed 550 mg/M2 (E. A. Lefrak et al., Cancer, 32:302, 1973). Even at or near the recommended maximum total cumulative dosage (430–650 mg/M2) significant and persistent heart dysfunction occurs in 60% of patients and 14% develop congestive heart failure. (A. Dresdale et al., Cancer, 52:51, 1983). Thus, while these drugs are useful to inhibit the growth of cancerous tumors, the patient may die of congestive heart failure because of the severe cardiotoxic side effect of the drugs.
It has also been found that the cardiotoxicity of these anthracyclines is produced by the metabolic reduction of the 13-keto moiety to a 13-dihydro alcohol metabolite (P. S. Mushlin et al., Fed. Proc., 45:809, 1986). In test systems where doxorubicin is not metabolized appreciably to the 13-dihydro alcohol metabolite (doxorubicinol) no significant cardiotoxic effects are observed (P. S. Mushlin et al., Fed. Proc., 44:1274, 1985; R. D. Olson et al., Fed. Proc., 45:809, 1986). In contrast, the 13-dihydro metabolites, doxorubicinol and daunorubicinol, produce cardiotoxicity in these same test systems at relatively low concentrations (1–2 micrograms/ml, R. D. Olson et al., Proceed. Am. Assoc. Cancer Res., 26:227, 1985; R. D. Olson et al., Proceed Am. Assoc. Cancer Res. 28:441, 1987).
If doxorubicin is allowed to remain in the test systems even for short periods of time some metabolic conversion occurs and the 13-dihydro metabolite is formed in sufficient quantity so that cardiotoxicity begins to develop (L. Rossini et al., Arch. Toxicol. Suppl., 9:474, 1986; M. Del Tocca et al., Pharmacol. Res. Commun., 17:1073, 1985). Substantial evidence has, thus, accumulated that the cardiotoxicity of drugs such as doxorubicin and daunorubicin results from the potent cardiotoxic effects produced by their 13-dihydro metabolites (P. Mushlin et al., FASEB Journal, 2:A1133, 1988; R. Boucek et al., J. Biol. Chem., 262:15851, 1987; and R. Olson et al., Proc. Natl. Acad. Sci., 85:3585, 1988).
More recently it has been discovered that the 13-deoxy forms of doxorubicin, daunorubicin, or other similar anthracyclines will not be metabolically converted to cardiotoxic 13-dihydro forms, and that the 5-keto group can be modified to a form that will be less likely to generate free radicals, thus providing additional improved safety. In particular, see WO99/08687, U.S. Pat. Nos. 5,984,896 and 5,942,605 and PCT/US99/04704, disclosures of which are incorporated herein by reference.
The first documented process for preparing certain 13-deoxy anthracyclines from 13-p-methylbenzenesulfonylhydrazone anthracyclines had relatively low yields, on the order of about 10% (see Smith, et al., J. Med. Chem. 1978 21, 280–283). Improved processes for synthesizing 13-deoxy anthracyclines from 13-p-methylbenzenesulfonylhydrazone anthracyclines exhibiting enhanced yields are disclosed in WO99/08687 and U.S. Pat. No. 5,984,896. However, these processes employ a relatively large excess of reagents and take a relatively long time to carry out. Moreover, the yields, although increased, are less than optimum for commercial production. Furthermore, the use of 13-p-methylbenzenesulfonylhydrazone anthracyclines results in about 3% or more of this starting material in the 13-deoxy anthracycline product. The use of 13-p-F-benzenesulfonylhydrazone anthracyclines is known, but the synthesis of 13-p-F-, 13-p-Cl-, or 13-p-nitrobenzenesulfonylhydrazone anthracyclines from their parent 13-keto anthracyclines produce lower yields compared to 13-p-methylbenzenesulfonylhydrazone anthracyclines, and also produce lower yields of 13-deoxy anthracyclines.